Targeting the BCL-2 family in malignancies of germinal centre origin

The germinal centre is a dynamic microenvironment where B-cell responses are honed. Antigen-specific cells undergo clonal expansion followed by antibody affinity maturation and class switching through somatic hypermutation and recombination of immunoglobulin genes respectively. The huge proliferative capacity of the B-cells and the potential for generating nonfunctional or autoreactive immunoglobulins, necessitate strict control measures. Pro-apoptotic signalling pathways via B-cell receptors, FAS and the TGF-beta receptor, ALK5, ensure that apoptosis of germinal centre B-cells is the norm and cells only survive to differentiate fully if they receive sufficient pro-survival signals to overcome their 'primed for death' status. Several of the B-cell signalling pathways converge on the intrinsic apoptotic machinery to control expression of the BCL-2 family of apoptosis regulators including BIM, the pro-survival factor BCL-X-L and the BH3-only protein, BIK (recently identified as a mediator of a TGF-beta-induced default apoptosis pathway in human B-cells). It is a foreseeable hazard that cells undergoing genetic mutation and recombination events might unintentionally target some of these factors, resulting in defective programmed cell death. Here we discuss the function of BCL-2 family proteins in germinal centre reactions, their deregulation in malignancies of germinal centre origin, and the potential for targeting BCL-2-related proteins therapeutically in lymphomas.